Immune checkpoint blockade in CNS tumors

Published on February 29, 2016   48 min
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DAVID REARDON: Hello, my name is David Reardon. And I'm the clinical director of the Center for Neural Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts in the United States. Thank you for joining us for this Henry Stewart Talk on immune checkpoint blockade in central nervous system tumors.
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On the first slide, I've summarized the outcome for patients with glioblastoma in 2016. On the upper part of the slide, we see the standard of care therapy for newly diagnosed glioblastoma patients that includes maximum safe surgical resection, followed by radiation with daily temozolomide, after which patients receive five day temozolomide adjuvant cycles every 28 days for 6 to 12 cycles. And we see on the right that the outcome with this standard of care, which was established over 10 years ago, leaves a lot of room for improvement. The median progression free survival is only about eight months for patients, which means they're about 2/3 of the way through their planned treatment, and the average patient is already progressing. Unfortunately median survival is only about 15 to 18 months. Inevitably patients recur. And the historical outcome for patients with recurrent glioblastoma is summarized in the lower half of this slide where we see data from a series meta-analyses of clinical trials conducted through various cooperative groups in North America and in Europe. And what we see is that the outcome with the salvage therapies utilized in these clinical trials, which include various chemotherapeutic regimens, biologically-based targeted therapies, and a variety of other innovative strategies, unfortunately have yielded very poor outcome with six month progression free survival rates typically, approximately 10%. With the use of bevacizumab, the prototypical VEGF blocking anti-angiogenic agent, we can improve progression-free survival with a six month BFS rate of up to 40%. But this still leaves much room for improvement. And unfortunately bevacizumab does not improve overall survival.
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We see the development of immunotherapy over the past 120 years from pioneering work led by Dr. William Coley, a bone sarcoma surgeon at Memorial Sloan-Kettering, where he noted his patients who developed infections postoperatively had an improved outcome compared to patients who didn't develop infections. And this led him to reason that there may be something associated with these infections and the associated response of the immune system that led to better control of the tumor and outcome for patients. He then began a series of experiments where he injected bacterial toxins into the tumor or into patients as a strategy to improve their outcome, these so-called Coley's toxins. Now in the past 120 years, much work has gone on to help us better understand the role of immunotherapy in cancer and how the immune system interacts with cancers. And much of that work has culminated in a series of very exciting developments that have led to very dramatic improvements in outcome for a series of cancers. And this work culminated in the journal Science, identifying cancer immunotherapy as the breakthrough of the year in 2013. This is a summary of the recent approvals in the United States
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by the Food and Drug Administration of immunotherapies for cancer indications. And the first of these occurred in 2010. But we see from this table that rapidly accruing number of approvals have occurred, particularly in the last year to a year and a half. Most of these approvals are involving immune checkpoint inhibitors, which will be the focus of today's talk for brain cancer. And we see the approvals have come through for a variety of different cancer indications. For those who are not familiar with immune checkpoint inhibitors,
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these are a series of naturally occurring molecules that are present and activated any time our immune system is responding to a foreign threat. The inhibitory immune checkpoint molecules, indicated by the red dots in this graphic on the left of the slide, are specifically in place to naturally decrease the immune response once it's been activated. These molecules prevent the immune system's activation from extending too long or potentially harming normal tissues in the body. The two most well known and understood inhibitory immune checkpoint molecules are cytotoxic T-lymphocyte antigen 4, or CTLA-4, and programmed death-1 and its ligand, PD-L1. CTLA-4 and PD-1 are activated when the immune system is responding to attack of foreign or invading material in the body. And they downregulate that immune response, much like the brakes and the clutch in a manual transmission. The next slide highlights an important point
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Immune checkpoint blockade in CNS tumors

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